Quinazoline derivatives as medicaments

ABSTRACT

The invention is directed to methods to inhibit TGF-βand/or p38-α kinase using compounds of the formula  
                 
 
     or the pharmaceutically acceptable salts thereof  
     wherein R 3  is a noninterfering substituent;  
     each Z is CR 2  or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;  
     each R 2  is independently a noninterfering substituent;  
     L is a linker;  
     n is 0 or 1;and  
     Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

FIELD OF THE INVENTION

[0001] The invention relates to treating various disorders associatedwith enhanced activity of kinase p38-α and/or transforming growth factorbeta (TGF-β). More specifically, it concerns compounds that are relatedto quinazoline as useful in these methods.

BACKGROUND ART

[0002] A large number of chronic and acute conditions have beenrecognized to be associated with perturbation of the inflammatoryresponse. A large number of cytokines participate in this response,including IL-1, IL-6, IL-8 and TNF. It appears that the activity ofthese cytokines in the regulation of inflammation rely at least in parton the activation of an enzyme on the cell signaling pathway, a memberof the MAP kinase family generally known as p38 and alternatively knownas CSBP and RK. This kinase is activated by dual phosphorylation afterstimulation by physiochemical stress, treatment with lipopolysaccharidesor with proinflammatory cytokines such as IL- 1 and TNF. Therefore,inhibitors of the kinase activity of p38 are useful antiinflammatoryagents.

[0003] Transforming growth factor-beta (TGF-β) denotes a family ofproteins, TGF-β1, TGF-β2, and TGF-β3, which are pleiotropic modulatorsof cell growth and differentiation, embryonic and bone development,extracellular matrix formation, hematopoiesis, immune and inflammatoryresponses (Roberts and Sporn Handbook of Experimental Pharmacology(1990) 95:419-58; Massague et al. Ann Rev Cell Biol(1990) 6:597-646).Other members of this superfamily include activin, inhibin, bonemorphogenic protein, and Mullerian inhibiting substance. TGF-β initiatesan intracellular signaling pathway leading ultimately to the expressionof genes that regulate the cell cycle, control proliferative responses,or relate to extracellular matrix proteins that mediate outside-in cellsignaling, cell adhesion, migration and intercellular communication.

[0004] Therefore, inhibitors of the TGF-β intracellular signalingpathway are useful treatments for fibroproliferative diseases.Specifically, fibroproliferative diseases include kidney disordersassociated with unregulated TGF-β activity and excessive fibrosisincluding glomerulonephritis (GN), such as mesangial proliferative GN,immune GN, and crescentic GN. Other renal conditions include diabeticnephropathy, renal interstitial fibrosis, renal fibrosis in transplantpatients receiving cyclosporin, and HIV-associated nephropathy. Collagenvascular disorders include progressive systemic sclerosis, polymyositis,scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or thoseassociated with the occurrence of Raynaud's syndrome. Lung fibrosesresulting from excessive TGF-β activity include adult respiratorydistress syndrome, idiopathic pulmonary fibrosis, and interstitialpulmonary fibrosis often associated with autoimmune disorders, such assystemic lupus erythematosus and scleroderma, chemical contact, orallergies. Another autoimmune disorder associated withfibroproliferative characteristics is rheumatoid arthritis.

[0005] Eye diseases associated with a fibroproliferative conditioninclude retinal reattachment surgery accompanying proliferativevitreoretinopathy, cataract extraction with intraocular lensimplantation, and post glaucoma drainage surgery.

[0006] PCT applications WO98/06715, WO98/07425, and WO 96/40143, all ofwhich are incorporated herein by reference, describe the relationship ofp38 kinase inhibitors with various disease states. As mentioned in theseapplications, inhibitors of p38 kinase are useful in treating a varietyof diseases associated with chronic inflammation. These applicationslist rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions, sepsis, septic shock,endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma,adult respiratory distress syndrome, stroke, reperfusion injury, CNSinjuries such as neural trauma and ischemia, psoriasis, restenosis,cerebral malaria, chronic pulmonary inflammatory disease, silicosis,pulmonary sarcosis, bone resorption diseases such as osteoporosis,graft-versus-host reaction, Crohn's Disease, ulcerative colitisincluding inflammatory bowel disease (IBD) and pyresis.

[0007] The above-referenced PCT applications disclose compounds whichare p38 kinase inhibitors said to be useful in treating these diseasestates. These compounds are either imidazoles or are indoles substitutedat the 3- or 4-position with a piperazine ring linked through acarboxamide linkage. Additional compounds which are conjugates ofpiperazines with indoles are described as insecticides in WO97/26252,also incorporated herein by reference.

[0008] The compounds of the invention are quinazoline derivatives. Otherquinazoline compounds for other uses have been described. U.S. Pat. No.5,721,237 assigned to Rhone-Poulenc Rorer is directed to methods forselective treatment of cell growth and differentiation characterized byactivity of human epidermal growth factor receptor type II usingquinazoline substituted only in the 4-position with an aromatic moietyoptionally coupled to the quinazoline through a linking moiety. U.S.Pat. No. 4,480,883 describes compounds that exhibit tyrosine kinaseinhibition activity wherein the heterocyclic portion of a quinazoline orother fused ring nitrogen-containing aromatic system is substituted onlyonce with an aromatic moiety, again optionally coupled through a linker.U.S. Pat. No. 5,616,582 assigned to Zeneca describes tyrosine kinaseinhibitors which are quinazolines linked through an amino group at the4-position to a substituted or unsubstituted phenyl. These compoundscontain no substituents at position 2. U.S. Pat. No. 5,475,001 alsoassigned to Zeneca describes similar compounds with the same activity.U.S. Pat. No. 5,430,148 assigned to Agouron Pharmaceutical describesantiproliferative substituted quinazolinones and their counterpartswherein the keto group is replaced by a sulfone.

[0009] U.S. Pat. No. 5,719,157 to Takeda Chemical Industries describespharmaceutical compositions for inhibiting bone resorption which include4-phenyl quinoline derivatives which may further be substituted at the2-position with an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group.

[0010] None of the foregoing patents describes quinazoline derivativeswhich specifically inhibit p38-α or TGF-β.

DISCLOSURE OF THE INVENTION

[0011] The invention is directed to methods and compounds useful intreating conditions that are characterized by enhanced p38-α activityand/or TGF-β activity. These conditions include inflammation,proliferative diseases, and certain cardiovascular disorders as furtherdescribed below.

[0012] Compounds of the invention have been found to inhibit p38 kinase,the α-isoform in particular, and/or TGF-β and are thus useful intreating diseases mediated by these activities. The compounds of theinvention are of the formula

[0013] or the pharmaceutically acceptable salts thereof

[0014] wherein R³ is a noninterfering substituent;

[0015] each Z is CR² or N, wherein no more than two Z position ring Aare N, and wherein two adjacent Z positions in ring A cannot be N;

[0016] each R² is independently a noninterfering substituent;

[0017] L is a linker;

[0018] n is 0 or 1; and

[0019] Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic,aromatic or heteroaromatic moiety optionally substituted with 1-3noninterfering substituents.

[0020] The invention is directed to methods of treating inflammation orproliferative conditions using these compounds. The invention is alsodirected to treating conditions associated with cardiac failure usingthe invention compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIGS. 1A-1C show the structures of compounds prepared accordingto the methods of the invention and useful in the invention methods.

MODES OF CARRYING OUT THE INVENTION

[0022] The compounds of formula (1) are useful in treating conditionswhich are characterized by overactivity of p38 kinase, in particular theα-isoform and/or overactivity of TGF-β. Conditions “characterized byenhanced p38-α activity” include those where this enzyme is present inincreased amount or wherein the enzyme has been modified to increase itsinherent activity, or both. Conditions “characterized by enhanced TGF-βactivity” include those wherein TGF-β synthesis is stimulated so thatTGF-β is present in enhanced amount or wherein TGF-β latent protein isundesirably activated or converted to active TGF-β protein or whereinTGF-β receptors are upregulated or wherein the TGF-β protein showsenhanced binding to cells or extracellular matrix in the location of thedisease. Thus, in either case, “enhanced activity” refers to anycondition wherein the effectiveness of either of these proteins isundesirably high, regardless of the cause.

[0023] The compounds of the invention are useful in conditions whereeither p38-α kinase or TGF-β shows enhanced activity since thesecompounds inhibit the activities of both proteins. This is particularlyadvantageous in conditions which are characterized by enhancedactivities of both proteins. These conditions are those in whichfibrosis and organ sclerosis are caused by, or accompanied by,inflammation, oxidation injury, hypoxia, altered temperature orextracellular osmolarity, conditions causing cellular stress, apoptosisor necrosis. These conditions include ischemia-reperfusion injury,congestive heart failure, progressive pulmonary and bronchial fibrosis,hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis,interstitial renal fibrosis, chronic scarring diseases of the eyes,bladder and reproductive tract, bone marrow dysplasia, chronicinfectious or autoimmune states and traumatic or surgical wounds. Theseconditions, of course, would be benefited by compounds which inhibiteither TGF-β or p38-α. They are especially benefited by treatment withcompounds that inhibit both. Methods of treatment with the compounds ofthe invention are further discussed below.

[0024] The Invention Compounds

[0025] The compounds useful in the invention are derivatives ofquinazoline and related compounds containing mandatory substituents atpositions corresponding to the 2- and 4-positions of quinazoline. Ingeneral, a quinazoline nucleus is preferred, although alternativeswithin the scope of the invention are also illustrated below. Preferredembodiments for Z³ are N and CH; preferred embodiments for Z⁵-Z⁸ areCR². However, each of Z⁵-Z⁸ can also be N, with the proviso noted above.Thus, with respect to the basic quinazoline type ring system, preferredembodiments include quinazoline per se, and embodiments wherein all ofZ⁵-Z⁸ as well as Z³ are either N or CH. Also preferred are thoseembodiments wherein Z³ is N, and either Z⁵ or Z⁸ or both Z⁵ and Z⁸ are Nand Z⁶ and Z⁷ are CH or CR². Where R² is other than H, it is preferredthat CR² occur at positions 6 and/or 7.

[0026] As used herein, a “noninterfering substituent” is a substituentwhich leaves the ability of the compound of formula (1) to inhibit p38-αactivity and/or TGF-β activity qualitatively intact. Thus, thesubstituent may alter the degree of inhibition and the balance betweenp38-α inhibition and TGF-β inhibition. However, as long as the compoundof formula (1) retains the ability to inhibit either p38-α or TGF-βactivity or both, the substituent will be classified as“noninterfering.”

[0027] As used herein, “hydrocarbyl residue” refers to a residue whichcontains only carbon and hydrogen. The residue may be aliphatic oraromatic, straight-chain, cyclic, branched, saturated or unsaturated.The hydrocarbyl residue, when indicated, may contain heteroatoms overand above the carbon and hydrogen members of the substituent residue.Thus, when specifically noted as containing such heteroatoms, thehydrocarbyl residue may also contain carbonyl groups, amino groups,hydroxyl groups and the like, or contain heteroatoms within the“backbone” of the hydrocarbyl residue.

[0028] As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight- and branched-chain and cyclic monovalent substituents.Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl,2-propenyl, 3-butynyl, and the like. Typically, the alkyl, alkenyl andalkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl oralkynyl). Preferably they contain 1-6C (alkyl) or 2-6C (alkenyl oralkynyl). Heteroalkyl, heteroalkenyl and heteroalkynyl are similarlydefined but may contain 1-2 O, S or N heteroatoms or combinationsthereof within the backbone residue.

[0029] As used herein, “acyl” encompasses the definitions of alkyl,alkenyl, alkynyl and the related hetero-forms which are coupled to anadditional residue through a carbonyl group.

[0030] “Aromatic” moiety refers to a monocyclic or fused bicyclic moietysuch as phenyl or naphthyl; “heteroaromatic” also refers to monocyclicor fused bicyclic ring systems containing one ore more heteroatomsselected from O, S and N. The inclusion of a heteroatom permitsinclusion of 5-membered rings as well as 6-membered rings. Thus, typicalaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl,benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl,thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like.Any monocyclic or fused ring bicyclic system which has thecharacteristics of aromaticity in terms of electron distributionthroughout the ring system is included in this definition. Typically,the ring systems contain 5-12 ring member atoms.

[0031] Similarly, “arylalkyl” and “heteroalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1-6C. These carbon chains mayalso include a carbonyl group, thus making them able to providesubstituents as an acyl moiety.

[0032] With respect to the substituent at the positions corresponding tothe 4-position of quinazoline, LAr′, L is present or absent and is alinker which spaces the substituent Ar′ from ring B at a distance of 2-8Å, preferably 2-6 Å, more preferably 2-4 Å. The distance is measuredfrom the ring carbon in ring B to which one valence of L is attached tothe atom of the Ar′ cyclic moiety to which the other valence of thelinker is attached. The Ar′ moiety may also be coupled directly to ringB (i.e., when n is 0). Typical, but nonlimiting, embodiments of L are ofthe formula S(CR² ₂)_(m), —NR¹SO₂(CR² ₂)₁, NR¹(CR² ₂)_(m), NR¹CO(CR²₂)_(l), O(CR² ₂)_(m), OCO(CR² ₂)_(l), and

[0033] wherein Z is N or CH and wherein m is 0-4 and l is 0-3,preferably 1-3 and 1-2, respectively. L preferably provides —NR¹—coupled directly to ring B. A preferred embodiment of R¹ is H, but R¹may also be acyl, alkyl, arylacyl or arylalkyl where the aryl moiety maybe substituted by 1-3 groups such as alkyl, alkenyl, alkynyl, acyl,aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂,SR, —SOR, —NRSOR, —NRSO₂R, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR,—OCONR₂, —RCO, —COOR, —SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, whereineach R is independently H or alkyl (1-4C), preferably the substituentsare alkyl (1-6C), OR, SR or NR₂ wherein R is H or lower alkyl (1-4C).More preferably, R¹ is H or alkyl (1-6C). Any aryl groups contained inthe substituents may further be substituted by for example alkyl,alkenyl, alkynyl, halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR,—NRCONR₂, —NRCOOR, —OCONR₂, —RCO, —COOR, SO₂R, NRSOR, NRSO₂R, —SO₃R,—CONR₂, SO₂NR₂, CN, CF₃, or NO₂, wherein each R is independently H oralkyl (1-4C).

[0034] Ar′ is aryl, heteroaryl, including 6-5 fused heteroaryl,cycloaliphatic or cycloheteroaliphatic. Preferably Ar′ is phenyl, 2-, 3-or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, benzimidazolyl, indolyl,preferably each optionally substituted with a group selected from thegroup consisting of optionally substituted alkyl, alkenyl, alknyl, aryl,N-aryl, NH-aroyl, halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂,SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl(1-4C).

[0035] Ar′ is more preferably indolyl, 6-pyrimidyl, 3- or 4-pyridyl, oroptionally substituted phenyl.

[0036] For embodiments wherein Ar′ is optionally substituted phenyl,substituents include, without limitation, alkyl, alkenyl, alkynyl, aryl,alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR,—SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, RCO, —COOR,—SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independentlyH or alkyl (1-4C). Preferred substituents include halo, OR, SR, and NR₂wherein R is H or methyl or ethyl. These substituents may occupy allfive positions of the phenyl ring, preferably 1-2 positions, preferablyone position. Embodiments of Ar′ include substituted or unsubstitutedphenyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 6-pyrimidyl, indolyl,isoquinolyl, quinolyl, benzinmidazolyl, benzotriazolyl, benzothiazolyl,benzofuranyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,imidazolyl, and morpholinyl. Particularly preferred as an embodiment ofAr′ is 3- or 4-pyridyl, especially 4-pyridyl in unsubstituted form.

[0037] Any of the aryl moieties, especially the phenyl moieties, mayalso comprise two substituents which, when taken together, form a 5-7membered carbocyclic or heterocyclic aliphatic ring.

[0038] Thus, preferred embodiments of the substituents at the positionof ring B corresponding to 4-position of the quinazoline include2-(4-pyridyl)ethylamino; 4-pyridylamino; 3-pyridylamino; 2-pyridylamino;4-indolylamino; 5-indolylamino; 3-methoxyanilinyl;2-(2,5-difluorophenyl)ethylamino-, and the like.

[0039] R³ is generally a hydrocarbyl residue (1-20C) containing 0-5heteroatoms selected from O, S and N. Preferably R³ is alkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, eachunsubstituted or substituted with 1-3 substituents. The substituents areindependently selected from a group that includes halo, OR, NR₂, SR,—SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, RCO, —COOR, —SO₃R, NRSOR, NRSO₂R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or alkyl (1-4C) and with respect to any aryl orheteroaryl moiety, said group further including alkyl (1-6C) or alkenylor alknyl. Preferred embodiments of R³ (the substituent at positioncorresponding to the 2-position of the quinazoline) comprise a phenylmoiety optionally substituted with 1-2 substituents preferably halo,alkyl (1-6C), OR, NR₂, and SR wherein R is as defined above. Thus,preferred substituents at the 2-position of the quinazoline includephenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl,4-fluorophenyl and the like. Other preferred embodiments of R³ comprisea cyclopentyl or cyclohexyl moiety.

[0040] As noted above, R² is a noninterfering substituent. As set forthabove, a “noninterfering substituent” is one whose presence does notsubstantially destroy the p38-α kinase inhibiting ability and/or TGF-βinhibiting ability of the compound of formula (1).

[0041] Each R² is also independently a hydrocarbyl residue (1-20C)containing 0-5 heteroatoms selected from 0, S and N. Preferably, R² isindependently H, alkyl, alkenyl, alkenyl, acyl or hetero-forms thereofor is aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, eachunsubstituted or substituted with 1-3 substituents selectedindependently from the group consisting of alkyl, alkenyl, alkynyl,aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂,SR, —SOR, —SO₂ R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, NRSOR, NRSO₂R,—OCONR₂, RCO, —COOR, —SO₃R, NRSOR, —NRSO₂R, —CONR₂, SO₂NR₂, CN, CF₃, andNO₂, wherein each R is independently H or alkyl (1-4C). The aryl oraroyl groups on said substituents may be further substituted by, forexample, alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR,—NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, RCO, —COOR, —SO₃R, —CONR₂, SO₂NR₂,CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C).More preferably the substituents on R² are selected from R⁴, halo, OR⁴,NR₂, SR⁴, —OOCR⁴, —NROCR⁴, —COOR⁴, R⁴CO, —CONR⁴ ₂, —SO₂NR₂, CN, CF₃, andNO₂, wherein each R⁴ is independently H, or optionally substituted alkyl(1-6C), or optionally substituted arylalkyl (7-12C) and wherein two R⁴or two substituents on said alkyl or arylalkyl taken together may form afused aliphatic ring of 5-7 members.

[0042] R₂ may also, itself, be selected from the group consisting ofhalo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, NRSOR,NRSO₂R, —OCONR₂, RCO, —COOR, —SO₃R, NRSOR, NRSO₂R, —CONR₂, SO₂NR₂, CN,CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C).

[0043] More preferred substituents represented by R² are those as setforth with regard to the phenyl moieties contained in Ar′ or R³ as setforth above. Two adjacent CR² taken together may form a carbocyclic orheterocyclic fused aliphatic ring of 5-7 atoms. Preferred R²substituents are of the formula R⁴, —OR⁴, SR⁴ or R⁴NH—, especiallyR⁴NH—, wherein R⁴ is defined as above. Particularly preferred areinstances wherein R⁴ is substituted arylalkyl.

[0044] The compounds of formula (1) may be supplied in the form of theirpharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent on the compound of formula (1), the compound may also besupplied as a salt with a pharmaceutically acceptable cation.

[0045] Synthesis of the Invention Compounds

[0046] The compounds of the invention may be synthesized from thecorresponding 4-halo-2-phenyl quinazoline as described in ReactionScheme 1; which may be obtained from the corresponding4-hydroxyquinazoline as shown in Reaction Scheme 2. Alternatively, thecompounds can be prepared using anthranylamide as a starting materialand benzoylating the amino group followed by cychzation to obtain theintermediate 2-phenyl-4-hydroxy quinazoline as shown in Reaction Scheme3. Reaction Schemes 4-6 are similar to Reaction Scheme 3 except that anappropriate pyridine or 1,4-pyrimidine nucleus, substituted with acarboxamide residue and an adjacent amino residue, is substituted forthe anthranylimide. The compounds of the invention wherein R¹ is H canbe further derivatized to comprise other embodiments of R¹ as shown inReaction Scheme 7.

[0047] Reaction Scheme 1 is illustrative of the simple conversion of ahalogenated quinazoline to compounds of the invention. Of course, thephenyl of the illustration at position 2 may be generalized as R³ andthe 4-pyridylamino at position 2 can be generalized to Ar′—L or Ar′—.

[0048] Reaction Scheme 2 can, of course, be generalized in the samemanner as set forth for Reaction Scheme 1.

[0049] Again, Reaction Scheme 3 can be generalized by substituting thecorresponding acyl halide, R³COCl for the parafluorobenzoyl chloride.Further, Ar′ or Ar′—L may be substituted for 4-aminopyridine in the laststep.

[0050] It is seen that Reaction Scheme 1 represents the last step ofReaction Schemes 2-6 and that Reaction Scheme 2 represents the last twosteps of Reaction Scheme 3-6.

[0051] Reaction Scheme 7 provides conditions wherein compounds offormula (1) are obtained wherein R¹ is other than H.

[0052] Reaction Scheme 8 is a modification of Reaction Scheme 3 whichsimply demonstrates that substituents on ring A are carried through thesynthesis process. The principles of the behavior of the substituentsapply as well to Reactions Schemes 4-6.

[0053] Reaction Scheme 8 shows a modified form of Reaction Scheme 3which includes substituents R² in the quinazoline ring of formula (1).The substituents are carried throughout the reaction scheme. In step a,the starting material is treated with thionyl chloride in the presenceof methanol and refluxed for 12 hours. In step b, the appropriatesubstituted benzoyl chloride is reacted with the product of step a bytreating with the appropriately substituted benzoyl chloride in pyridinefor 24 hours. In embodiments wherein X (shown illustratively in theortho-position) is fluoro, 2-fluorobenzoyl chloride is used as areagent; where X is (for illustration ortho-chloro), 2-chlorobenzoylchloride is used.

[0054] In step c, the ester is converted to the amide by treating inammonium hydroxide in an aprotic solvent such as dimethyl formamide(DMF) for 24 hours. The product is then cyclized in step d by treatmentwith 10 N NaOH in ethanol and refluxed for 3 hours.

[0055] The resulting cyclized form is then converted to the chloride instep e by treating with thionyl chloride in chloroform in the presenceof a catalytic amount of DMF under reflux for 4 hours. Finally, theillustrated 4-pyridylamino compound is obtained in step f by treatingwith 4-amino pyridine in the presence of potassium carbonate and DMF andrefluxed for 2 hours.

[0056] In illustrative embodiments of Reaction Scheme 8, R² may, forexample, provide two methoxy substituents so that the starting materialis 2-amino-4,5-dimethoxy benzoic acid and the product is, for example,2-(2-chlorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline.

[0057] In another illustrative embodiment, R² provides a single nitro;the starting material is thus, for example, 2-amino-5-nitrobenzoic acidand the resulting compound is, for example,2(2-fluorophenyl)4-(4-pyridylamino)-5-nitroquinazoline.

[0058] Reaction Schemes 4-6 can be carried out in a manner similar tothat set forth in Reaction Scheme 8, thus carrying along R² substituentsthrough the steps of the process.

[0059] In compounds of the invention wherein R² is nitro, the nitrogroup may be reduced to amino and further derivatized as indicated inReaction Scheme 9.

[0060] In Reaction Scheme 9, the illustrative product of Reaction Scheme8 is first reduced in step g by treating with hydrogen and palladium oncarbon (10%) in the presence of acetic acid and methanol at atmosphericpressure for 12 hours to obtain the amino compound. The resulting aminocompound is either converted to the acyl form (R═acyl) using theappropriate acid chloride in the presence of chloroform and pyridine forfour hours, or is converted to the corresponding alkylated amine(R═alkyl) by treating the amine intermediate with the appropriatealdehyde in the presence of ethanol, acetic acid, and sodiumtriacetoxyborohydride for 4 hours.

[0061] While the foregoing exemplary Reaction Schemes are set forth toillustrate the synthetic methods of the invention, it is understood thatthe substituents shown on the quinazoline ring of the products aregenerically of the formula (1) as described herein and that thereactants may be substituted accordingly. Variations to accommodatevarious substituents which represent embodiments of R³ other than themoieties shown in these illustrative examples or as Ar′ in theseillustrative examples may also be used. Similarly, embodiments whereinthe substituent at position 4 contains an arylalkyl can be used in theseschemes. Methods to synthesize the compounds of the invention are, ingeneral, known in the art.

[0062] Administration and Use

[0063] The compounds of the invention are useful among other indicationsin treating conditions associated with inflammation. Thus, the compoundsof formula (1) or their pharmaceutically acceptable salts are used inthe manufacture of a medicament for prophylactic or therapeutictreatment of mammals, including humans, in respect of conditionscharacterized by excessive production of cytokines and/or inappropriateor unregulated cytokine activity on such cells as cardiomyocytes,cardiofibroblasts and macrophages.

[0064] The compounds of the invention inhibit the production ofcytokines such as TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of the inventionare shown herein to inhibit a member of the MAP kinase family variouslycalled p38 MAPK (or p38), CSBP, or SAPK-2. The activation of thisprotein has been shown to accompany exacerbation of the diseases inresponse to stress caused, for example, by treatment withlipopolysaccharides or cytokines such as TNF and IL-1. Inhibition of p38activity, therefore, is predictive of the ability of a medicament toprovide a beneficial effect in treating diseases such as coronary arterydisease, congestive heart failure, cardiomyopathy, myocarditis,vasculitis, restenosis, such as occurs following coronary angioplasty,atherosclerosis, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, multiplesclerosis, acute respiratory distress syndrome (ARDS), asthma, chronicobstructive pulmonary disease (COPD), silicosis, pulmonary sarcosis,sepsis, septic shock, endotoxic shock, toxic shock syndrome, heart andbrain failure (stroke) that are characterized by ischemia andreperfusion injury, surgical procedures, such as transplantationprocedures and graft rejections, cardiopulmonary bypass, coronary arterybypass graft, CNS injuries, including open and closed head trauma,inflammatory eye conditions such as conjunctivitis and uveitis, acuterenal failure, glomerulonephritis, inflammatory bowel diseases, such asCrohn's disease or ulcerative colitis, graft vs host disease, boneresorption diseases like osteoporosis, type II diabetes, pyresis,psoriasis, cachexia, viral diseases such as those caused by HIV, CMV,and Herpes, and cerebral malaria.

[0065] Within the last several years, p38 has been shown to comprise agroup of MAP kinases designated p38-α, p38-β, p38-γ and p38-δ. Jiang, Y.et al. J Biol Chem (1996) 271:17920-17926 reported characterization ofp38-β as a 372-amino acid protein closely related to p38-α. In comparingthe activity of p38-α with that of p38-β, the authors state that whileboth are activated by proinflammatory cytokines and environmentalstress, p38-β was preferentially activated by MAP kinase kinase-6 (MKK6)and preferentially activated transcription factor 2, thus suggestingthat separate mechanisms for action may be associated with these forms.

[0066] Kumar, S. et al. Biochem Biophys Res Comm (1997) 235:533-538 andStein, B. et al. J Biol Chem(1997) 272:19509-19517 reported a secondisoform of p38-β, p38-β2, containing 364 amino acids with 73% identityto p38-α. All of these reports show evidence that p38- β is activated byproinflammatory cytokines and environmental stress, although the secondreported p38-β isoform, p38-β2, appears to be preferentially expressedin the CNS, heart and skeletal muscle compared to the more ubiquitoustissue expression of p38-α. Furthermore, activated transcriptionfactor-2 (ATF-2) was observed to be a better substrate for p38-β2 thanfor p38-α, thus suggesting that separate mechanisms of action may beassociated with these forms. The physiological role of p38-β1 has beencalled into question by the latter two reports since it cannot be foundin human tissue and does not exhibit appreciable kinase activity withthe substrates of p38-α.

[0067] The identification of p38-γ was reported by Li, Z. et al. BiochemBiophys Res Comm (1996) 228:334-340 and of p38-δ by Wang, X., et al., JBiol Chem (1997) 272:23668-23674 and by Kumar, S., et al., BiochemBiophys Res Comm (1997) 235:533-538. The data suggest that these two p38isoforms (γ and δ) represent a unique subset of the MAPK family based ontheir tissue expression patterns, substrate utilization, response todirect and indirect stimuli, and susceptibility to kinase inhibitors.

[0068] Various results with regard to response to drugs targeting thep38 family as between p38-α and either the putative p38-β1 or p38-β2 orboth were reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A. et al. Chem and Biol (1995) 5:321-328. An additional paperby Wang, Y. et al. J Biol Chem (1998) 273:2161-2168 suggests thesignificance of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38-β activity results inhypertrophy, whereas activation of p38-α activity leads to myocyteapoptosis. Thus, selective inhibition of p38-α activity as compared top38-β activity will be of benefit in treating conditions associated withcardiac failure. These conditions include congestive heart failure,cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvulardisease, conditions associated with cardiopulmonary bypass, coronaryartery bypass, grafts and vascular grafts. Further, to the extent thatthe α-isoform is toxic in other muscle cell types, α-selectiveinhibitors would be useful for conditions associated with cachexiaattributed to TNF or other conditions such as cancer, infection, orautoimmune disease.

[0069] Thus, the invention encompasses the use of compounds whichselectively inhibit the activity of the p38-α isoform for treatingconditions associated with activation of p38-α, in particular thoseassociated with cardiac hypertrophy, ischemia or other environmentalstress such as oxidation injury, hyperosmolarity or other agents orfactors that activate p38-α kinase, or cardiac failure, for example,congestive heart failure, cardiomyopathy and myocarditis.

[0070] The TGF-β inhibition activity is useful in treatingfibroproliferative diseases, treating collagen vascular disorders,treating eye diseases associated with a fibroproliferative condition,venting excessive scarring, treating neurological conditions and otherconditions that are targets for TGF-β inhibitors and in preventingexcessive scarring that elicits and accompanies restenosis followingcoronary angioplasty, cardiac fibrosis occurring after infarction andprogressive heart failure, and in hypertensive vasculopathy, and keloidformation or hypertrophic scars occurring during the healing of woundsincluding surgical wounds and traumatic lacerations.

[0071] Neurological conditions characterized by TGF-β production includeCNS injury after traumatic and hypoxic insults, Alzheimer's disease, andParkinson's disease.

[0072] Other conditions that are potential clinical targets for TGF-βinhibitors include myelofibrosis, tissue thickening resulting fromradiation treatment, nasal polyposis, polyp surgery, liver cirrhosis,and osteoporosis.

[0073] Diseases benefited by TGF-β inhibition include cardiovasculardiseases such as congestive heart failure, dilated cardiomyopathy,myocarditis, or vascular stenosis associated with atherosclerosis,angioplasty treatment, or surgical incisions or mechanical trauma;kidney diseases associated with fibrosis and/or sclerosis, includingglomerulonephritis of all etiologies, diabetic nephropathy, and allcauses of renal interstitial fibrosis, including hypertension,complications of drug exposure, such as cyclosporin, HIV-associatednephropathy, transplant nephropathy, chronic ureteral obstruction;hepatic diseases associated with excessive scarring and progressivesclerosis, including cirrhosis due to all etiologies, disorders of thebiliary tree, and hepatic dysfunction attributable to infections such ashepatitis virus or parasites; syndromes associated with pulmonaryfibrosis with consequential loss of gas exchange or ability toefficiently move air into and out of the lungs, including adultrespiratory distress syndrome, idiopathic pulmonary fibrosis, orpulmonary fibrosis due to infectious or toxic agents such as smoke,chemicals, allergens, or autoimmune disease; all collagen vasculardisorders of a chronic or persistent nature including progressivesystemic sclerosis, polymyositis, scleroderma, dermatomyositis,fascists, or Raynaud's syndrome, or arthritic conditions such asrheumatoid arthritis; eye diseases associated with fibroproliferativestates, including proliferative vitreoretinopathy of any etiology orfibrosis associated with ocular surgery such as retinal reattachment,cataract extraction, or drainage procedures of any kind; excessive orhypertrophic scar formation in the dermis occurring during wound healingresulting from trauma or surgical wounds; disorders of thegastrointestinal tract associated with chronic inflammation, such asCrohn's disease or ulcerative colitis or adhesion formation as a resultof trauma or surgical wounds, polyposis or states post polyp surgery;chronic scarring of the peritoneum associated with endometriosis,ovarian disease, peritoneal dialysis, or surgical wounds; neurologicalconditions characterized by TGF-β production or enhanced sensitivity toTGF-β, including states post-traumatic or hypoxic injury, Alzheimer'sdisease, and Parkinson's disease; and diseases of the joints involvingscarring sufficient to impede mobility or produce pain, including statespost-mechanical or surgical trauma, osteoarthritis and rheumatoidarthritis.

[0074] The modulation of the immune and inflammation systems by TGF-β(Wahl et al. Immunol Today (1989) 10:258-61) includes stimulation ofleukocyte recruitment, cytokine production, and lymphocyte effectorfunction, and inhibition of T-cell subset proliferation, B-cellproliferation, antibody formation, and monocytic respiratory burst.TGF-β is a stimulator for the excess production of extracellular matrixproteins, including fibronectin and collagen. It also inhibits theproduction of enzymes that degrade these matrix proteins. The net effectis the accumulation of fibrous tissue which is the hallmark offibroproliferative diseases.

[0075] TGF-β is active as a homodimer, but is synthesized and secretedfrom cells as an inactive latent complex of the mature homodimer andproregions, called latency associated protein (LAP). These proteins bindto each other through noncovalent interactions (Lyons and Moses Eur JBiochem (1990) 187:467). LAP is often disulfide-linked to separate geneproducts, called latent TGF-β binding proteins or LTBPs. These latentforms provide stability for the mature cytokine and a means fortargeting it to the extracellular matrix and cell surfaces (Lawrence EurCytokine Network (1996) 7:363-74). Activation of the latent complexoccurs after secretion from cells and is believed to result from theaction of proteases, such as plasmin (lunger et al. Kidney Intl (1997)51:1376-82), on LAP, thrombospondin-1 binding (Crawford et al. Cell(1998) 93:1159-70), and binding to the integrin v6 (Munger et al. Cell(1999) 319-28).

[0076] Other than v6 there is a variety of cell surfaceproteins/receptors that transduce the signals initiated by binding ofthe active TGF-β ligand to its receptors. These include types I, II, I,IV, and V. Type IV is present only in the pituitary gland while theothers are ubiquitous. The binding affinities among the three isoformsfor the type I and II receptors differ such that these two receptorsbind TGF-β1 and TGF-β3 [?] more tightly than TGF-β2 (Massague Cell(1992) 69:1067-70).

[0077] The type IV receptor or endoglin has a similar isoform bindingprofile in contrast to the type III receptor, betaglycan, which bindsequally well to all three isoforms (Wang et al. Cell (1991) 67:797-805;Lopez-Casillas Cell (1991) 67:785-95). The type V receptor binds toIGFBP-3 and is thought to have an active kinase domain similar to thetype I and II receptors. Cloning of the type I and type II receptorsdemonstrated the existence of cytoplasmic serine/threonine kinasedomains (Wrana et al. Cell (1992) 71:1003-14; Lin et al. Cell (1992)68:775-85; Ibid. 71:1069; Massague Cell (1992) 69:1067-70). Initiationof the TGF-β signaling pathway results from the binding of the TGF-βligand to the extracellular domain of the type II receptor (Massague AnnRev Biochem (1998) 67:753-91). The bound receptor then recruits type Ireceptor into a multimeric membrane complex, whereupon theconstitutively active type II receptor kinase phosphorylates andactivates type I receptor kinase. The function of the type I receptorkinase is to phosphorylate a receptor-associated co-transcriptionfactor, smad-2/3, thereby releasing it into the cytoplasm where it bindsto smad4. This smad complex translocates into the nucleus, associateswith a DNA-binding cofactor, such as Fast-1, binds to enhancer regionsof specific genes, and activates transcription. The expression of thesegenes leads to the synthesis of cell cycle regulators that controlproliferative responses or extracellular matrix proteins that mediateoutside-in cell signaling, cell adhesion, migration, and intercellularcommunication.

[0078] The manner of administration and formulation of the compoundsuseful in the invention and their related compounds will depend on thenature of the condition, the severity of the condition, the particularsubject to be treated, and the judgement of the practitioner;formulation will depend on mode of administration. As the compounds ofthe invention are small molecules, they are conveniently administered byoral administration by compounding them with suitable pharmaceuticalexcipients so as to provide tablets, capsules, syrups, and the like.Suitable formulations for oral administration may also include minorcomponents such as buffers, flavoring agents and the like. Typically,the amount of active ingredient in the formulations will be in the rangeof 5%-95% of the total formulation, but wide variation is permitteddepending on the carrier. Suitable carriers include sucrose, pectin,magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

[0079] The compounds useful in the invention may also be administeredthrough suppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

[0080] The compounds may also be administered topically, for topicalconditions such as psoriasis, or in formulation intended to penetratethe skin. These include lotions, creams, ointments and the like whichcan be formulated by known methods.

[0081] The compounds may also be administered by injection, includingintravenous, intramuscular, subcutaneous or intraperitoneal injection.Typical formulations for such use are liquid formulations in isotonicvehicles such as Hank's solution or Ringer's solution.

[0082] Alternative formulations include nasal sprays, liposomalformulations, slow-release formulations, and the like, as are known inthe art.

[0083] Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

[0084] The dosages of the compounds of the invention will depend on anumber of factors which will vary from patient to patient. However, itis believed that generally, the daily oral dosage will utilize 0.001-100mg/kg total body weight, preferably from 0.01-50 mg/kg and morepreferably about 0.01 mg/kg-10 mg/kg. The dose regimen will vary,however, depending on the conditions being treated and the judgment ofthe practitioner.

[0085] It should be noted that the compounds of formula (1) can beadministered as individual active ingredients, or as mixtures of severalembodiments of this formula. In addition, the inhibitors of p38 kinaseor TGF-β, and dual inhibitors of p38kinase and TGF-β kinase, can be usedas single therapeutic agents or in combination with other therapeuticagents. Drugs that could be usefully combined with these compoundsinclude natural or synthetic corticosteroids, particularly prednisoneand its derivatives, monoclonal antibodies targeting cells of the immunesystem, antibodies or soluble receptors or receptor fusion proteinstargeting immune or non-immune cytokines, and small molecule inhibitorsof cell division, protein synthesis, or mRNA transcription ortranslation, or inhibitors of immune cell differentiation or activation.

[0086] As implicated above, although the compounds of the invention maybe used in humans, they are also available for veterinary use intreating animal subjects.

[0087] The following examples are intended to illustrate but not tolimit the invention.

EXAMPLE 1 Synthesis of 4-(4-Pyridvlamino)-2-Phenyl Quinazoline

[0088] This example illustrates Reaction Scheme 1.

[0089] A. 4-Chloro-2-phenyl quinazoline, 1 equivalent, was treated with1 equivalent 4-aminopyridine and 1 equivalent potassium carbonate indimethylformamide (DMF), under reflux for 4 hours. The reaction mixturewas cooled to room temperature and concentrated under vacuum to an oil.This crude material was dissolved in ethyl acetate and chromatographedusing hexane:ethyl acetate:methanol 8:2:0.5 to obtain solid product.Electron impact mass spectroscopy (EIMS) gave a molecular ioncorresponding to the calculated molecular weight of the title compound.

[0090] B. Using the procedure of paragraph A of the example butsubstituting the starting materials shown in Table 1 below for4-aminopyridine, the corresponding quinazolines shown in the table wereobtained. TABLE 1 Substitute for 4-amino pyridine Product obtained3-amino pyridine 2-phenyl-4-(3-pyridylamino)-quinazoline 2-aminopyridine 2-phenyl-4-(2-pyridylamino)-quinazoline 4-aminomethyl pyridine2-phenyl-4-(2-(4-pyridyl)methylamino)- quinazoline 3-aminomethylpyridine 2-phenyl-4-(2-(3-pyridyl)methylamino)- quinazoline2-aminomethyl pyridine 2-phenyl-4-(2-(2-pyridyl)methylamino)-quinazoline

EXAMPLE 2 Synthesis of 4-(4-Pyridylamino)-2-(4-Chlorophenyl) Quinazoline

[0091] This example illustrates Reaction Scheme 2.

[0092] A. 4-Chloro-2-(4-chlorophenyl) quinazoline:4-hydroxy-2-(4-chlorophenyl) quinazoline, 1 equivalent, was suspended inchloroform and treated with 12 equivalents of thionyl chloride in thepresence of a catalytic amount of dimethyl formamide, under reflux for 4hours. After removal of the solvents under reduced pressure, a solid wasobtained that was analyzed by thin layer chromatography and EIMS andfound to be 4-chloro-2-(4-chlorophenyl) quinazoline.

[0093] B. 4-(4-pyridylamino)-2-(4-chlorophenyl) quinazoline:4-chloro-2-(4-chlorophenyl) quinazoline, 1 equivalent, was treated with1 equivalent 4-aminopyridine and 1 equivalent potassium carbonate indimethylformamide (DMF), under reflux for 4 hours, as described inExample 1. The reaction mixture was worked up as in Example 1 andproduct confirmed by EIMS.

EXAMPLE 3 Synthesis of 4-(4-Pyridylamino)-2-(4-Fluorophenyl) Quinazoline

[0094] This example illustrates Reaction Scheme 3.

[0095] A. 4-Fluorobenzoyl anthranilamide: Anthranilamide, 1 equivalent,was dissolved in chloroform/pyridine (1:1) and treated with4-fluorobenzoyl chloride, 1.1 equivalent for one hour at roomtemperature. The reaction was concentrated under vacuum. The residue wastaken up in ethyl acetate and washed with 1 N aqueous sodium carbonate,10% aqueous hydrochloric acid, saturated sodium chloride solution anddried over anhydrous sodium sulfate. Concentration of the ethyl acetatelayer gave a white solid that was found to be homogenous by thin layerchromatography (TLC) and confirmed by EIMS.

[0096] B. 4-Hydroxy-2-(4-fluorophenyl) quinazoline: 4-fluorobenzoylanthranilamide, from paragraph A, 1 equivalent, was dissolved in ethanoland to this was added 10 N aqueous sodium hydroxide, 3.0 equivalents,and the resulting solution heated under reflux for 3 hours. The reactionmixture was cooled to room temperature and concentrated under vacuum.The residue was dissolved in an excess of water and acidified withconcentrated hydrochloric acid. A white precipitate forms uponacidification. This precipitate was filtered and washed extensively withwater. The solid was then dried under high vacuum in the presence ofdessicant. The solid was found to be homogenous by TLC and productconfirmed by EIMS.

[0097] C. 4-Chloro-2-(4-fluorophenyl) quinazoline:4-hydroxy-2-(4-fluorophenyl) quinazoline, from paragraph B, 1equivalent, was suspended in chloroform and treated with 12 equivalentsof thionyl chloride in the presence of a catalytic amount of dimethylformamide, under reflux for 4 hours. After removal of the solvents underreduced pressure a solid was obtained that was analyzed by TLC. EIMSconfirmed the desired product.

[0098] D. 4-(4-pyridylamino)-2-(4-fluorophenyl) quinazoline:4-chloro-2-(4-fluorophenyl) quinazoline from paragraph C was reacted asin Example 1 to obtain the title compound.

EXAMPLE 4 Synthesis of 2-Phenyl-4-(3-Methoxyanyl) Quinazoline

[0099] 4-Chloro-2-phenylquinazoline, 2 equivalents, 3-methoxyanilinyl, 2equivalents, and potassium carbonate, 2 equivalents, were dissolved in10 mL isopropanol and refluxed for 2 hours. The precipitated productformed was filtered and washed with water. Recrystallization frommethanol provided the product as a white solid that was found to behomogenous by thin layer chromatography (TLC) and confirmed by EIMS.

EXAMPLE 5 Synthesis of 4-(4-Methoxybenzyl-Pyridylamino)-2-PhenlQuinazoline

[0100] 4-(4-pyridylamino)-2-phenyl quinazoline, 1 equivalent, wasdissolved in reagent grade acetone, to this was added 5 equivalents ofpotassium hydroxide and 1.5 equivalents of 4-methoxybenzyl chloride. Themixture was refluxed under nitrogen for 4 hours. After cooling to roomtemperature the reaction mixture was concentrated and the residue takenup in ethyl acetate and washed with saturated aqueous sodium chlorideand dried over anhydrous sodium sulfate and concentrated to give an oil.This crude material was dissolved in ethyl acetate and chromatographedas in Example 1. EIMS confirmed the product.

EXAMPLE 6 Prepared Compounds of the Invention

[0101] The compounds in Table 2 shown below have been prepared using thereaction schemes and exemplary procedures set forth herein. In thecompounds of Table 2, Z⁵-Z⁸ are CH and Z³ is N; i.e., these are allquinazoline derivatives per se. The table thus lists the embodiments ofL, Ar and R³. TABLE 2 Compound No. L Ar^(′) R³  1 NH 4-pyridyl2-chlorophenyl  2 NH 4-pyridyl 2,6-dichlorophenyl  3 NH 4-pyridyl2-methylphenyl  4 NH 4-pyridyl 2-bromophenyl  5 NH 4-pyridyl2-fluorophenyl  6 NH 4-pyridyl 2,6-difluorophenyl  7 NH 4-pyridyl phenyl 8 NH 4-pyridyl 4-fluorophenyl  9 NH 4-pyridyl 4-methoxyphenyl 10 NH4-pyridyl 3-fluorophenyl 11* N* 4-pyridyl phenyl 12^(†) N^(†) 4-pyridylphenyl 13 NHCH₂ 4-pyridyl phenyl 14 NHCH₂ 4-pyridyl 4-chlorophenyl 15 NH3-pyridyl phenyl 16 NHCH₂ 2-pyridyl phenyl 17 NHCH₂ 3-pyridyl phenyl 18NHCH₂ 2-pyridyl phenyl 19 NHCH₂CH₂ 2-pyridyl phenyl 20 NH 6-pyrimidinylphenyl 21 NH 2-pyrimidinyl phenyl 22 NH phenyl phenyl 23 NHCH₂ phenyl3-chlorophenyl 24 NH 3-hydroxyphenyl phenyl 25 NH 2-hydroxyphenyl phenyl26 NH 4-hydroxyphenyl phenyl 27 NH 4-indolyl phenyl 28 NH 5-indolylphenyl 29 NH 4-methoxyphenyl phenyl 30 NH 3-methoxyphenyl phenyl 31 NH2-methoxyphenyl phenyl 32 NH 4-(2-hydroxyethyl)phenyl phenyl 33 NH3-cyanophenyl phenyl 34 NHCH₂ 2,5-difluorophenyl phenyl 35 NH4-(2-butyl)phenyl phenyl 36 NHCH₂ 4-dimethylaminophenyl phenyl 37 NH4-pyridyl cyclopentyl 38 NH 2-pyridyl phenyl 39 NHCH₂ 3-pyridyl phenyl40 NH 4-pyrimidyl phenyl 41^(‡) N^(‡) 4-pyridyl phenyl 42 NHp-aminomethylphenyl phenyl 43 NHCH₂ 4-aminophenyl phenyl 44 NH 4-pyridyl3-chlorophenyl 45 NH phenyl 4-pyridyl 46 NH

phenyl 47 NH 4-pyridyl t-butyl 48 NH 2-benzylamino-3-pyridyl phenyl 49NH 2-benzylamino-4-pyridyl phenyl 50 NH 3-benzyloxyphenyl phenyl 51 NH4-pyridyl 3-aminophenyl 52 NH 4-pyridyl 4-pyridyl 53 NH 4-pyridyl2-naphthyl 54

4-pyridyl phenyl 55

phenyl phenyl 56

2-pyridyl phenyl 57 NHCH₂CH₂

phenyl 58 not present

phenyl 59 not present

phenyl 60 NH 4-pyridyl cyclopropyl 61 NH 4-pyridyl 2-trifluoromethylphenyl 62 NH 4-aminophenyl phenyl 63 NH 4-pyridyl cyclohexyl 64 NH3-methoxyphenyl 2-fluorophenyl 65 NH 4-methoxyphenyl 2-fluorophenyl 66NH 4-pyrimidinyl 2-fluorophenyl 67 NH 3-amino-4-pyridyl phenyl 68 NH4-pyridyl 2-benzylaminophenyl 69 NH 2-benzylaminophenyl phenyl 70 NH2-benzylaminophenyl 4-cyanophenyl 71 NH 3′-cyano-2-benzylaminophenylphenyl

[0102] Compounds 1-37 in Table 2 have been assessed in terms of percentinhibition of p38-α activity in the presence of 15 μM concentration (SeeExample 7). The percent inhibition for all of these compounds ismeasurable, and is, for some compounds, as high as 100%.

[0103] The compounds in Table 3 contain modifications of the quinazolinenucleus as shown. These compounds have been prepared and tested fortheir ability to inhibit TGF-β and/or p38-α kinase. All of the compoundsin Table 3 are embodiments of formula (1) wherein Z³ is N and Z⁶ and Z⁷represent CH. In all cases the linker, L, is present and is NH. TABLE 3Compound No. Z⁵ Z⁸ Ar′ R³ 72 CH N 4-pyridyl 2-fluorophenyl 73 CH N4-pyridyl 2-chlorophenyl 74 CH N 4-pyridyl phenyl 75 N N 4-pyridylphenyl 76 N CH 4-pyridyl phenyl

[0104] Additional compounds were prepared wherein ring A contains CR² atZ⁶ or Z⁷ where R² is not H. These compounds, which are all quinazolinederivatives, wherein L is NH and Ar′ is 4-pyridyl, are shown in Table 4.In Table 4, the percent inhibition was measured at 15 μM compound (or at1 μM compound as indicated). See Example 7. Inhibitions above 90% wereobserved. TABLE 4 Compound No. R³ CR² as noted 77 2-chlorophenyl6,7-dimethoxy 78 2-fluorophenyl 6-nitro 79 2-fluorophenyl 6-amino  80**2-fluorophenyl 7-amino  81** 2-fluorophenyl 6-(3-methoxybenzylamino) 82** 2-fluorophenyl 6-(4-methoxybenzylamino) 83 2-fluorophenyl6-(2-isobutylamino) 84 2-fluorophenyl 6-(4-methylmercaptobenzylamino) 852-fluorophenyl 6-(4-methoxybenzoyl amino) 86 4-fluorophenyl 7-amino 874-fluorophenyl 7-(3-methoxybenzylamino)

EXAMPLE 7 Assay for p38 Kinase Inhibition

[0105] The compounds to be tested were solubilized in DMSO and dilutedinto water to the desired concentrations. The p38 kinase was diluted to10 μg/ml into a buffer containing 20 mM MOPS, pH 7.0, 25 mMbeta-glycerol phosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT.

[0106] The reaction was carried out by mixing 20 μl test compound with10 μl of a substrate cocktail containing 500 μg/ml peptide substrate and0.2 mM ATP (+200 μCi/ml gamma-32P-ATP) in a 4× assay buffer. Thereaction was initiated by the addition of 10 μl of p38 kinase. Finalassay conditions were 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerolphosphate, 80 mM KCl, 22 mM MgCl₂, 3 mM MgSO₄, 1 mg/ml gelatin, 0.625 mMEGTA, 1 mM DTT, 125 μg/ml peptide substrate, 50 μM ATP, and 2.5 μg/mlenzyme. After a 40 minute incubation at room temperature, the reactionwas stopped by the addition of 10 μl per reaction of 0.25 M phosphoricacid.

[0107] A portion of the reaction was spotted Qnto a disk of P81phosphocellulose paper, the filters were dried for 2 minutes and thenwashed 4× in 75 mM H₃PO₄. The filters were rinsed briefly in 95%ethanol, dried, then placed in scintillation vials with liquidscintillation cocktail.

[0108] Alternatively, the substrate is previously biotinylated and theresulting reactions are spotted on SAM²™ streptavidin filter squares(Promega). The filters are washed 4× in 2M NaCl, 4× in 2M NaCl with 1%phosphoric acid, 2× in water, and briefly in 95% ethanol. The filtersquares are dried and placed in scintillation vials with liquidscintillation cocktail.

[0109] Counts incorporated are determined on a scintillation counter.Relative enzyme activity is calculated by subtracting background counts(counts measured in the absence of enzyme) from each result, andcomparing the resulting counts to those obtained in the absence ofinhibitor.

[0110] IC₅₀ values were determined with curve-fitting plots availablewith common software packages. Approximate IC₅₀ values were calculatedusing formula

IC ₅₀(app)=A×i/(1−A)

[0111] where A=fractional activity and i=total inhibitor concentration.

[0112] The compounds in Table 5 have IC₅₀ in the range of 0.1-1.5 μM vsp38-α: TABLE 5 Compound No. Compound Name 16 2-phenyl-4-(4-pyridylmethylamino)-quinazoline 72-phenyl-4-(4-pyridylamino)-quinazoline 82-(4-fluorophenyl)-(4-pyridylamino)-quinazoline 12-(2-chlorophenyl)-(4-pyridylamino)-quinazoline 30 2-phenyl-4-(3-methoxyanilinyl)-quinazoline 52-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline 42-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline 32-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline 79 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-amino quinazoline

[0113] Compounds 5 and 7 were tested for their specificity for p38 byassessing their ability to inhibit other kinases. These compounds weretested at 50 μL and were soluble at 250 μM in 5% DMSO/95% water. Theresults are shown in Table 6. TABLE 6 IC₅₀ (app) - μM DNA-dep Compoundp38-γ JNK1 PKA PKC PK (PKD) cck2 EGF-R 5  227  167 >250 >100 120  2454.2 7 >300 >300  310 >500 240 >500 34

[0114] In Table 6, compound 5 is2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline and compound 7 is2-phenyl-4-(4-pyridylamino)- quinazoline.

[0115] As seen in Table 6, these compounds are highly specific forp38-α. In addition, these compounds were assessed with respect to p38-βand gave curve fitted values of IC₅₀ as follows: Compound 5: 0.928 μM;Compound 7: 3.65 μM.

1. A method to treat conditions characterized by enhanced p38-α activityand/or enhanced TGF-β activity, which method comprises administering toa subject in need of such treatment a compound of the formula:

or the pharmaceutically acceptable salts thereof wherein R³ is anoninterfering substituent; each Z is CR² or N, wherein no more than twoZ positions in ring A are N, and wherein two adjacent Z positions inring A cannot be N; each R² is independently a noninterferingsubstituent; L is a linker; n is 0 or 1; and Ar′ is the residue of acyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromaticmoiety optionally substituted with 1-3 noninterfering substituents: 2.The method of claim 1 wherein said condition is a proinflammationresponse or a fibroproliferative response or both.
 3. The method ofclaim 2 wherein said proinflammation response is multiple sclerosis,IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis, other arthritic conditions, sepsis, septic shock, endotoxicshock, Gram-negative sepsis, toxic shock syndrome, asthma, adultrespiratory distress syndrome, stroke, reperfusion injury, CNS injury,psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcosis, a bone resorption disease,graft-versus-host reaction, Crohn's Disease, ulcerative colitis, orpyresis.
 4. The method of claim 2 wherein said fibroproliferativeresponse is associated with a renal disorder, a vascular disorder, afibrosis, an autoimmune disorder, an eye disease, excessive scarring, aneurological condition, myelofibrosis, tissue thickening, nasalpolyposis, a polyp, liver cirrhosis, or osteoporosis.
 5. The method ofclaim 4 wherein said renal disorder, is glomerulonephritis, diabeticnephropathy, renal interstitial fibrosis, renal fibrosis in transplantpatients receiving cyclosporin, and HIV-associated nephropathy; andwherein said vascular disorder is progressive systemic sclerosis,polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis,morphea, or Raynaud's syndrome; and wherein said fibrosis is associatedwith adult respiratory distress syndrome, idiopathic pulmonary fibrosis,interstitial pulmonary fibrosis, cardiac fibrosis, keloid formation, orhypertrophic scarring; and wherein said autoimmune disorder is systemiclupus erythematosus, scleroderma, or rheumatoid arthritis; and whereinsaid eye disease is retinal detachment, cataracts, or glaucoma; andwherein said neurological condition is CNS injury, Alzheimer's disease,or Parkinson's disease.
 6. The method of claim 1 wherein R³ is ahydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O,S and N.
 7. The method of claim 6 wherein R³ is alkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, or heteroarylalkyl, each unsubstituted orsubstituted with 1-3 substituents.
 8. The method of claim 7 wherein saidsubstituents are independently selected from the group consisting ofhalo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR,—NRSOR, —NRSO₂R, —OCONR₂, RCO, —COOR, —SO₃R, —CONR₂, SO₂NR₂, CN, CF₃,and NO₂, wherein each R is independently H or alkyl (1-4C) and withrespect to any aryl or heteroaryl moiety, said group further includingalkyl (1-6C).
 9. The method of claim 1 wherein said substituents onsubstituted Ar are independently selected from the group consisting ofoptionally substituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl,N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR,—NRCOR, —NRCONR₂, —NRCOOR, —NRSOR, —NRSO₂R, —OCONR₂, RCO, —COOR, —SO₃R,—CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H oralkyl (1-4C), and wherein any aryl or aroyl groups on said substituentsmay be further. substituted by alkyl, alkenyl, alkynyl, halo, OR, NR₂,SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —NRSOR, —NRSO₂R,—OCONR₂, RCO, —COOR, —SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, whereineach R is independently H or alkyl (1-4C).
 10. The method of claim 9wherein Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 4-pyrimidyl, indolyl,isoquinolyl, quinolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl,benzofuranyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,imidazolyl, or morpholinyl, all of which may optionally be substituted.11. The method of claim 1 wherein each R² is independently a hydrocarbylresidue (1-20C) containing 0-5 heteroatoms selected from O, S and N. 12.The method of claim 11 wherein each R² is independently H, alkyl,alkenyl, alkynyl, acyl or hetero-forms thereof or is aryl, arylalkyl,heteroalkyl, heteroaryl, or heteroarylalkyl, each unsubstituted orsubstituted with 1-3 substituents selected independently from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl,NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR,—NRCONR₂, —NRCOOR, —NRSOR, —NRSO₂R, —OCONR₂, RCO, —COOR, —SO₃R, —CONR₂,SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl(1-4C), and wherein any aryl or aroyl groups on said substituents may befurther substituted by alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —SOR,—SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —NRSOR, —NRSO₂R, —OCONR₂, RCO,—COOR, —SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or alkyl (1-4C), or R₂ is selected from the groupconsisting of halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂,—NRCOOR, NRSOR, NRSO₂R, —OCONR₂, RCO, —COOR, —SO₃R, NRSOR, NRSO₂R,—CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H oralkyl (1 -4C).
 13. The method of claim 11 wherein said substituents onR² are independently selected from the group consisting of R⁴, halo,OR⁴, NR₂, SR⁴, —OOCR⁴, —NROCR⁴, —COOR⁴, R⁴CO, —CONR⁴ ₂, —SO₂NR₂, CN,CF₃, and NO₂, wherein each R⁴ is independently H, or optionallysubstituted alkyl (1-6C), or optionally substituted arylalkyl (7-12C)and wherein two R⁴ or two substituents on said alkyl or arylalkyl takentogether may form a fused aliphatic ring of 5-7 members.
 14. The methodof claim 1 wherein n is 0 or n is 1 and L is a bivalent residue thatprovides a distance of 2-8 Å between ring B and Ar′.
 15. The method ofclaim 14 wherein L is S(CR² ₂)_(m), —NR¹SO₂(CR² ₂)_(l), SO₂(CR² ₂)_(m),SO₂NR¹(CR² ₂)_(l), NR³(CR² ₂)_(m), NR¹CO(CR² ₂)_(l), O(CR² ₂)_(m), orOCO(CR² ₂)_(l),

wherein Z is N or CH and wherein m is 0-4 and l is 0-3; R¹ is H, alkylor arylalkyl where the aryl moiety may be substituted by 1-3substituents selected independently from the group consisting of alkyl,alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl,NH-aroyl, halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂,—NRCOOR, —NRSOR, —NRSO₂R, —OCONR₂, RCO, —COOR, —SO₃R, —CONR₂, SO₂NR₂,CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4 C);and wherein any aryl or aroyl groups on said substituents may be furthersubstituted by alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —SOR, —SO₂R,—OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —NRSOR, —NRSO₂R, —OCONR₂, RCO, —COOR,—SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NR₂, wherein each R is independentlyH or alkyl (1-4C); and R² is as defined in claim
 12. 16. The method ofclaim 1 wherein the compound of formula (1) is selected from the groupconsisting of compounds 1-87 herein.
 17. The method of claim 1 whereinthe compound of formula (1) is selected from the group consisting ofcompounds shown in FIGS. 1A-1C herein.
 18. A pharmaceutical compositionfor treating conditions characterized by enhanced p38-α activity and/orenhanced TGF-β activity which composition comprises a therapeuticallyeffective amount of a compound of the formula

or the pharmaceutically acceptable salts thereof wherein R³ is anoninterfering substituent; each Z is CR² or N, wherein no more than twoZ positions in ring A are N, and wherein two adjacent Z positions inring A cannot be N; each R² is independently a noninterferingsubstituent; L is a linker; n is 0 or 1; and Ar′ is the residue of acyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromaticmoiety optionally substituted with 1-3 noninterfering substituents inadmixture with at least one pharmaceutically acceptable excipient. 19.The composition of claim 18 which further contains an additionaltherapeutic agent.
 20. The composition of claim 19 wherein saidadditional therapeutic agent is a corticosteroid, a monoclonal antibody,or an inhibitor of cell division.
 21. A compound of the formula:

and the pharmaceutically acceptable salts thereof wherein each R² isindependently a noninterfering substituent; m is an integer of 0-4; Z isCH; R¹ is alkyl (1-6C) or arylalkyl optionally substituted on the arylgroup with 1-3 substituents independently selected from alkyl (1-6C),halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, —SO₂NR₂, CN, CF₃,and NO₂, wherein each R is independently H or lower alkyl (1-4C); n is0, 1 or 2; and (a) Ar is phenyl, substituted with at least one groupselected from the group consisting of optionally substituted alkyl(1-6C), halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, SO₂NR₂,CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl(1-4C), or pyridyl, indolyl, or pyrimidyl, each optionally substitutedwith at least one group selected from the group consisting of optionallysubstituted alkyl (1-6C), halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR,—CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H orlower alkyl (1-4C); and R³ is a branched or cyclic alkyl group (5-7C) oris phenyl optionally substituted with 1-2 substituents whichsubstituents are selected from the group consisting of alkyl (1-6C),halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, —SO₂NR₂, CN, CF₃,and NO₂, wherein each R is independently H or lower alkyl (1-4C); or (b)Ar is phenyl, pyridyl, indolyl, or pyrimidyl, each optionallysubstituted with a group selected from the group consisting ofoptionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —OOCR, —NROCR,RCO, —COOR, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or lower alkyl (1 -4C); and R³ is a branched or cyclicalkyl group (5-7C) or is phenyl substituted with 1-2 substituents whichsubstituents are selected from the group consisting of alkyl (1-6C),halo, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, —SO₂NR₂, CN, and CF₃,wherein each R is independently H or lower alkyl (1-4C); or (c) Ar isphenyl substituted with a group selected from the group consisting ofoptionally substituted NR₂, SR, —NROCR, RCO, —CONR₂, SO₂NR₂, CN, andCF₃, wherein each R is independently H or lower alkyl (1-4C); or pyridylsubstituted with a group selected from the group consisting ofoptionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —OOCR, —NROCR,RCO, —COOR, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or lower alkyl (1-4C); or indolyl or pyrimidyl, eachoptionally substituted with a group selected from the group consistingof optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —OOCR,—NROCR, RCO, —COOR, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or lower alkyl (1-4 C); and R³ is a branched or cyclicalkyl group (5-7C) or is phenyl optionally substituted with 1-2substituents which substituents are selected from the group consistingof allyl (1-6C), halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂,—SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or loweralkyl (1-4C); or (d) Ar is phenyl, pyridyl, indolyl, or pyrimidyl, eachoptionally substituted with a group selected from the group consistingof optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —OOCR,—NROCR, RCO, —COOR, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or lower alkyl (1-4C); and R³ is a branched or cyclicalkyl group (5-7C) or is phenyl substituted with 1-2 substituents whichsubstituents are selected from the group consisting of alkyl (1-6C),halo, OR, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, —SO₂NR₂, CN, CF₃, andNO₂, wherein each R is independently H or lower alkyl (1-4C).
 22. Thecompound of claim 1 which is selected from the group consisting of2-phenyl-4-(4-pyridylamino)-quinazoline;2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline;2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline;2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline;2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(3-methoxyanilyl)-4-(4-pyridylamino)-quinazoline;2-(2,6-dichlorophenyl)-4-(4-pyridylarnino)-quinazoline;2-(2,6-dibromophenyl)-4-(4-pyridylamino)-quinazoline;2-(2,6-difluorophenyl)-4-(4-pyridylamino)-quinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;2-(4-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-6-nitroquinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino -6-aminoquinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-7-aminoquinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(3-methoxybenzylamino)-quinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methoxybenzylamino)-quinazoline;2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(2-isobutylamino)-quinazoline;and2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methylmercaptobenzylamino)-quinazoline.